Identification of a Novel C5L2 Variant (S323I) in a French Canadian Family With Familial Combined Hyperlipemia

Abstract

Objective-A functional acylation stimulating protein (ASP) receptor, C5L2, has been recently identified in ASPresponsive cells. Impaired ASP-mediated triglyceride synthesis has previously been described in a subset of hyperapolipoprotein B/familial combined hyperlipidemia subjects. Methods and Results-DNA sequencing of C5L2 coding region in 61 unrelated probands identified a heterozygous variant (G9683 T) in 1 subject, resulting in Ser3233 Ile substitution in the carboxyl terminal region. This variant was not detected in 2176 additional chromosomes by restriction fragment length polymorphism or fluorescence polarization genotyping. Eight family members of the proband were identified with one altered (ϩ/Ϫ)C5L2 allele. Nine other family members had the wild-type (ϩ/ϩ)C5L2 sequence. The abnormal allele was associated with increased plasma triglyceride, plasma cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein B and ASP. Of 23 subjects tested in cell-based ASP bioactivity assays, those with C5L2(ϩ/Ϫ) variant (nϭ2) had a 50% reduction in ASP-stimulated triglyceride synthesis, glucose transport and marked reduction in maximal binding (B max ). By contrast, a C5L2(ϩ/ϩ) family member responded normally, as did hyperapolipoprotein B normal ASP subjects compared with C5L2(ϩ/ϩ) controls (nϭ6). Key Words: acylation stimulating protein Ⅲ adipose Ⅲ C3adesArg Ⅲ gene defect Ⅲ G protein-coupled receptor Ⅲ hyperapolipoprotein B Ⅲ triglyceride synthesis I ncreased plasma apolipoprotein B (apoB) is a common dyslipoproteinemia associated with coronary artery disease 1 and is an excellent marker for diagnosis and treatment monitoring. 2 The hallmark is increased low-density lipoprotein (LDL) particles with overproduction of hepatic apoB 3 and increased small dense LDL particles. 4 Within this group, familial combined hyperlipidemia is considered to be the most frequent lipoprotein disorder in premature coronary artery disease (CAD). 5 The lipoprotein pattern varies in time and the level of penetrance may be incomplete, especially in premenopausal women. The pathogenesis of familial combined hyperlipidemia is complex and is very similar to that encountered in the metabolic syndrome. 6 This has hampered research in the cause of the disorder. Studies from Genest et al 7 and Castro-Cabezas et al 8 showed that hyperapolipoprotein B (hyperapoB) subjects have delayed triglyceride (TG) clearance and increased fatty acid after an oral fat load. 9 Peripheral resistance to fatty acid uptake in adipose tissue leads to increased hepatic flux, stimulating lipoprotein production. 10 We have proposed that, in a subset of patients, a defect in adipose tissue storage (particularly postprandially) might contribute to these abnormalities. Conclusion-TheIn support of this hypothesis, acylation stimulating protein (ASP) is a potential candidate. ASP binds to adipocytes and preadipocytes, promotes triglyceride synthesis through stimulation of both glucose transport and fatty acid esterification, 11,12 indirectly enhancing the action ...

Adipokines and the Immune System: An Adipocentric View

“…A similar phenotype of delayed postprandial lipid clearance and altered lipid metabolism was obtained in wildtype mice injected for 10 days with either anti-C5L2 or anti-ASP neutralizing antibodies (Cui et al 2007). Finally, in humans a C5L2 mutation has been associated with alterations in lipid metabolism (Marcil et al 2006).…”

International Union of Basic and Clinical Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors

“…Two SNP possibly linked to fatty acid metabolism have been identified in the human C5AR2 gene. First, SNP 968G/T, causing an amino acid exchange of S323I, was found associated with inheritable combined hyperlipemia in a French Canadian family, but could not be identified in a screening that involved Han, Uygur, and Kazakh subjects with familial hyperlipemia or type 2 diabetes (Cui et al, 2009b;Marcil et al, 2006;Zheng et al, 2011a). Second, a recently discovered 698C/T substitution, leading to a P233L amino acid exchange, appears to be a genetic marker of coronary artery disease and type 2 diabetes mellitus in the Han and Uygur populations in northwestern China (Zheng et al, 2011b(Zheng et al, , 2012.…”

Detection and Treatment of Children and Adolescents with Dyslipidemia

“…A defect in ASP-mediated TG synthesis was previously described in a subset of hyperapoB/FCHL subjects. One of the 61 unrelated proband had a heterozygous variant (c.G968T) in C5L2, resulting in p.Ser323lle substitution in the carboxyl terminal region [42]. Eight family members of the proband were identified with one altered (±) C5L2 allele.…”